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0026-895X/97/040683-09$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 52:683-691 (1997).

Differential A1 Adenosine Receptor Reserve for Two Actions of Adenosine on Guinea Pig Atrial Myocytes

Miduturu Srinivas, John C. Shryock, Donn M. Dennis, Stephen P. Baker, and Luiz Belardinelli

Departments of Pharmacology (M.S., S.P.B., L.B.), Medicine (J.C.S., L.B.), and Anesthesiology (D.M.D), University of Florida, Gainesville, Florida 32610

Adenosine activates adenosine-induced inwardly rectifying K+ current (IKAdo) and inhibits isoproterenol (100 nM)-stimulated L-type Ca2+ current (beta -ICa,L) of guinea pig atrial myocytes with EC50 values of 2.17 and 0.20 µM, respectively. We determined whether this 11-fold difference in potency of adenosine is due to the existence of a greater A1 adenosine receptor reserve for the inhibition of beta -ICa,L than for the activation of IKAdo. Atrial myocytes were pretreated with vehicle (control) or the irreversible A1 adenosine receptor antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulfonyl)benzoyl]oxy]propyl]-1-propylxanthine (FSCPX) (10 and 50 nM) for 30 min, and after a 60-min washout period, concentration-response curves were determined for the adenosine-induced activation of IKAdo and inhibition of beta -ICa,L. Pretreatment of atrial myocytes with 10 nM FSCPX reduced the maximal activation of IKAdo by 60% (7.9 ± 0.2 to 3.2 ± 0.1 pA/pF). In contrast, a higher concentration of FSCPX (50 nM) was required to reduce the maximal inhibition of beta -ICa,L by 39% (95 ± 4% to 58.7 ± 5.6%) and caused a 15-fold increase in the EC50 value of adenosine. Values of the equilibrium dissociation constant (KA) for adenosine to activate IKAdo and inhibit beta -ICa,L, estimated according to the method of Furchgott, were 2.7 and 5.6 µM, respectively. These values were used to determine the relationship between adenosine receptor occupancy and response. Half-maximal and maximal activations of IKAdo required occupancies of 40% and 98% of A1 adenosine receptors, respectively. In contrast, occupancies of only 4% and 70%, respectively, of A1 adenosine receptors were sufficient to cause half-maximal and maximal inhibitions of beta -ICa,L. Consistent with this result, a partial agonist of the A1 adenosine receptor SHA040 inhibited beta -ICa,L by 60 ± 3.5% but activated IKAdo by only 18.1 ± 2.5%. The results indicate that the A1 adenosine receptor is coupled more efficiently to an inhibition of beta -ICa,L than to an activation of IKAdo.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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